Tackling the vascular herterogeneity issue in tumors: identification of novel targets for tumor therapy.


Contains fulltext : 74485.pdf (publisher's version ) (Open Access)This thesis focuses on the identification of novel vascular targeting agents directed against tumor endothelium and the expression patterns of their targets in (clinical) tumor samples. Tumors obtain their blood supply by the formation of new vessels and/or by the incorporation, and possibly subsequent modulation, of pre-existent vessels. The latter ones may be unsusceptible to anti-angiogenic therapy. Therefore, induction of coagulation in the existing tumor vascular bed is an attractive adjuvant approach to anti-angiogenesis to deprive tumor cells from blood. This requires that tumor vessel targeting agents that specifically recognize the entire heterogeneous tumor vasculature become available. We identified Plexin D1 as a novel tumor vascular target. This membrane protein is expressed on both angiogenic and activated co-opted tumor vasculature, as well as on tumor cells in a wide range of clinical solid tumors of different origin. In addition, Plexin D1 expression is correlated with tumor invasion and metastasis in human melanocytic lesions. We isolated nanobodies against Plexin D1 which were able to specifically target tumor blood vessels in mice carrying brain lesions of angiogenic melanoma. The heterogeneity of tumor vasculature requires the identification of additional agents that, in combination, target the entire tumor vasculature. By in vivo biopanning of both naive and immune Llama phage display libraries in orthotopic mouse xenograft models of glioma which display vessel heterogeneity we isolated various tumor vessel recognizing nanobodies, also against incorporated pre-existent vessels blood vessels. Importantly, by using one of these nanobodies as bait in yeast two hybrid screens we identified dynactin-1-p150glued as its interacting ligand. We show that the use of immune nanobody phage libraries, in combination with appropriate animal models of cancer, and yeast-two-hybrid screens with appropriate prey libraries, is a very powerful platform for the identification of novel tumor vessel targeting agents and their binding partners.RU Radboud Universiteit Nijmegen, 11 november 2009Promotor : Krieken, J.H.J.M. van Co-promotor : Leenders, W.P.J.192 p

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